ABSTRACT - Overall This revised application is in response to the U19 funding opportunity for the Midlife in the United States (MIDUS) study. The mission of MIDUS is to study health, broadly defined, as an integrated biopsychosocial process that unfolds across the decades of adult life. The baseline study was begun in 1995 with over 7,000 adults, including twins, aged 25 to 74. This sample has been followed for 20 years, and along the way, MIDUS was augmented with city-specific sample of African Americans, and more recently, a newly recruited national sample, known as the MIDUS Refresher. Using a multi-project design, comprehensive survey, biomedical, and neuroscience data have been collected on MIDUS respondents. In addition, current P01 funding of MIDUS has facilitated the completion of a 3rd wave of survey data and 2nd wave of cognitive data. We seek funds in this application to collect longitudinal data for the Daily Diary Project, the Biomarker Project, and the Neuroscience Project. We also request funds to initiate a new Gene Expression Project focused on the expression of genes central to the body's immune-inflammatory response as well as a Retention-Early Warning Project, designed to reinstate a portion of drop-outs from prior waves of data collection. These five projects are supported by an Administrative Core, a Bio Core, and a Statistics Core. Across all projects and cores, detailed responses have been assembled in response to concerns raised in the prior review. In addition, the Overall Plan documents the enormous momentum that has grown up around the MIDUS study via updates on data usage and scientific productivity, including the high volume of new publications (88) generated just since this application was first submitted ten months ago. MIDUS fills a unique niche among NIA-supported longitudinal studies, given its wide age expanse and its unusual depth in psychosocial, biomarker, and neuroscience assessments, which permit a focus on the neurobiological mechanisms and pathways through which sociodemographic and psychosocial factors influence unfolding profiles of health and illness. A unique strength is the thematic focus on psychosocial strengths, which are being used to explicate profiles of resilience in many adults confronted with varieties of adversity. MIDUS also includes a national twin sample, thus offering unique opportunities to advance knowledge of the interplay of genetic and environmental factors in understanding healthy or unhealthy aging. Importantly, MIDUS has captured the attention of the scientific community: it is the most frequently downloaded study at the National Archive of Computerized Data on Aging (NACDA). Nearly 700 publications have been generated, many breaking new ground in forging linkages among sociodemographic, psychosocial, and neurobiological factors to account for differing pathways to later life morbidity and mortality.